RESEARCH ARTICLE

Fractionated Stereotactic Gamma KnifeRadiosurgery for Large Brain Metastases: ARetrospective, Single Center StudyJoo Whan Kim1,2, Hye Ran Park1,2, Jae Meen Lee1,2, Jin Wook Kim1,2, Hyun-Tai Chung1,2,

Dong Gyu Kim1,2, Hee-Won Jung1,2, Sun Ha Paek1,2*

1 Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea, 2 Department

of Neurosurgery, Seoul National University Hospital, Seoul, Korea

* paekshny@daum.net

Abstract

Purpose

Stereotactic radiosurgery (SRS) is widely used for brain metastases but has been relatively

contraindicated for large lesions (>3 cm). In the present study, we analyzed the efficacy

and toxicity of hypofractionated Gamma Knife radiosurgery to treat metastatic brain tumors

for which surgical resection were not considered as the primary treatment option.

Methods and Materials

Thirty-six patients, forty cases were treated with Gamma Knife-based fractionated SRS for

three to four consecutive days with the same Leksell frame on their heads. The mean gross

tumor volume was 18.3 cm, and the median dose was 8 Gy at 50% isodose line with 3 frac-

tions for three consecutive days (range, 5 to 11 Gy and 2 to 4 fractions for 2 to 4 consecu-

tive days). Survival rates and prognostic factors were analyzed.

Results

The overall survival rate at one and two years was 66.7 and 33.1%, respectively. The

median survival time was 16.2 months, and the local control rate was 90%. RTOG toxicity

grade 1 was observed in 3 (8.3%) patients, grade 2 in 1 (2.7%) patient and grade 3 in 1

(2.7%) patient respectively. Radiation necrosis was developed in 1 (2.7%) patient. KPS

scores and control of primary disease resulted in significant differences in survival.

Conclusions

Our findings suggest that consecutive hypofractionated Gamma Knife SRS could be

applied to large metastatic brain tumors with effective tumor control and low toxicity rates.

PLOS ONE | DOI:10.1371/journal.pone.0163304 September 23, 2016 1 / 12

a11111

OPENACCESS

Citation: Kim JW, Park HR, Lee JM, Kim JW,

Chung H-T, Kim DG, et al. (2016) Fractionated

Stereotactic Gamma Knife Radiosurgery for Large

Brain Metastases: A Retrospective, Single Center

Study. PLoS ONE 11(9): e0163304. doi:10.1371/

journal.pone.0163304

Editor: Deric M. Park, National Cancer Institute,

UNITED STATES

Received: April 24, 2016

Accepted: September 7, 2016

Published: September 23, 2016

Copyright: © 2016 Kim et al. This is an open

access article distributed under the terms of the

Creative Commons Attribution License, which

permits unrestricted use, distribution, and

reproduction in any medium, provided the original

author and source are credited.

Data Availability Statement: Data are available

upon request due to ethical restrictions regarding

patient privacy. Requests for the data may be sent

to the corresponding author.

Funding: This study was supported by the Korea

Institute of Planning & Evaluation for Technology in

Food, Agriculture, Forestry, and Fisheries, Republic

of Korea (311011-05-3-SB020); by the Korea

Healthcare Technology R&D Project

(HI11C21100200) funded by Ministry of Health &

Welfare, Republic of Korea; by the Technology

Innovation Program (10050154, Business Model

Introduction

Metastatic brain tumors are the most common intracranial tumors, outnumbering primarybrain tumors and occurring in up to 25–30% of cancer patients.[1] The natural course of thesepatients are approximately 1 month survival without any intervention.[2] Aside from chemo-therapy, the treatment options for brain metastases include steroid medication, surgical resec-tion, whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS).Corticosteroid treatment alone results in a median survival of 2 months; the median survivalwithWBRT is 4 to 6 months, while for surgical resection of a single lesion, the median survivalis 9 to 14 months.[3–6] Brain metastases are often inoperable because of their location, multi-plicity, comorbidity, and performance status.[7] SRS has resulted in local control rates of 71 to96% and a median survival of 7 to 13.5 months in previous studies.[8–11] Traditionally, theindication for SRS has been a lesion diameter of 3 cm or less, and large size is a relative contra-indication due to treatment-related toxicity.[12] The concept of fractionation was first intro-duced in radiotherapy to reduce the toxicity of treatment for large tumors. Similar efficacy andlower toxicity risk of fractionated radiotherapy compared with single dose SRS has been dem-onstrated in several studies.[13–15] Previous reports have only studied LINAC-based SRS;however, Gamma Knife-based SRS has been rarely reported.[16, 17]In this study we analyzed the efficacy and toxicity of hypofractionated Gamma Knife radio-

surgery in the treatment of large metastatic brain tumors. Our hypothesis was that hypofractio-nated radiosurgery has equal effectiveness and tolerable toxicity rates.

Patients and Methods

Between January 2010 and July 2015, 70 patients with a total of 79 lesions of brain metastaseswere treated with Gamma Knife-based fractionated radiosurgery. The patient selection criteriafor fractionation treatment instead of single fractionwere lesions greater than 14 cm3 or lesionsgreater than 10 cm3 located in posterior fossa. Because it is known that lesions greater than 3cm in diameter is relative contraindication for single fraction radiosurgery due to risk foredema after treatment.[12] Therefore, 25 patients with lesions greater than 14 cm3 and 11patients with posterior fossa lesions with volume greater than 10 cm3 were included in thestudy. There were no patient exclusion criteria for number of metastases or previous radiationtreatment. The patient and treatment characteristics are summarized in Table 1. Patients weretreated with hypofractionated radiosurgery instead of surgery due to the location of the lesion,poor general condition (age, comorbidities) and the wishes of the patients. The median age ofthe patients was 56 years at the time of treatment; there were 16 men and 20 women. The his-tology of the primary tumors included lung cancer, breast cancer, colorectal cancer and others.A solitarymetastasis was present in 17 patients, while multiple metastases occurred in 19.Patients with multiple metastases were treated with single fraction radiosurgery for othersmaller lesions. Primary disease was controlled in 25 patients. The median Karnofsky perfor-mance status (KPS) was 90, ranging from 60 to 100. Recursive partitioning analysis (RPA) andgraded prognostic assessment (GPA) were analyzed. The mean gross tumor volume was 18.3cm3. All data were obtained from hospital chart and imaging study databases; the study wasapproved by the Institutional ReviewBoard. (IRB no. 1508-084-695) Patients and relativeswere informed about the role, limitation and toxicities of radiosurgery. The requirement forobtaining informed consent from the patients was waived because the study was only based onthe information obtained as a part of routine clinical care and their medical records. Allpatients received IV dexamethasone 10 mg on admission, followed by a maintenance dose of 4mg every 6 hours for 3 consecutive days until the end of radiosurgery;oral prednisolone was

Fractionated GKS for Brain Metastases

PLOS ONE | DOI:10.1371/journal.pone.0163304 September 23, 2016 2 / 12

Development for Personalized Medicine Based on

Integrated Genome and Clinical Information)

funded by the Ministry of Trade, Industry & Energy

(MI, Korea); and by the Bio & Medical Technology

Development Program of the NRF funded by the

Korean government, MSIP (2015M3C7A1028926).

Competing Interests: The authors have declared

that no competing interests exist.

Table 1. Patient characteristics and treatment parameters.

Characteristics Value

Number of patients 36

Age (years)

Median 56

< 65 27 (75)

� 65 9 (25)

Gender

Male 16 (44.4)

Female 20 (55.6)

Primary cancer

Non-small cell lung cancer 10 (27.8)

Breast cancer 10 (27.8)

Colorectal cancer 5 (13.9)

Renal cell carcinoma 2 (5.5)

Othersa 9 (25)

Previous treatment

None 22 (61.1)

WBRT 8 (22.2)

Radiosurgery 6 (16.7)

Number of metastasis

1 17 (47.2)

2–3 12 (33.3)

>4 7 (19.5)

Primary disease

Uncontrolled 21 (58.3)

Controlled 15 (41.7)

Karnofsky performance status

Median 90

Range 60–100

RTOG RPA class

1 6 (16.7)

Others 30 (8)

GPA score

0–1 7 (19.4)

1.5–2.5 18 (50)

3–4 11 (30.6)

SRS dose (Gy)

8 * 3 fractions 24 (66.6)

Others 12 (33.3)

Gross tumor volume (cm3)

10–14 11 (30.6)

>14 25 (69.4)

Mean 18.3

Range 10.0–50.3

Prescribed tumor volume (cm3)

Mean 21.2

Range 11.5–67.8

(Continued )

Fractionated GKS for Brain Metastases

PLOS ONE | DOI:10.1371/journal.pone.0163304 September 23, 2016 3 / 12

then tapered over one week but was prolonged if symptoms caused by peritumoral edema per-sisted. Prophylactic antiepileptic medication was not used.Leksell Gamma Knife-based radiosurgerywas performed (Elekta Instrument AB, Stock-

holm, Sweden, Model Perfexion). The treatment plan utilized the Leksell Gamma Plan (version8.3.1, 10.1.0, 10.1.1, Elekta Instrument) system with thin-sectionmagnetic resonance imaging(MRI). T1–weighted images with gadolinium enhancement were used to determine the targetvolume. The radiosurgery isodose and marginal dose prescribedwere initially determinedbased on the tumor volume calculated during dose planning, using the best-fit isodosemethod;the prescription volume covered 95 to 99% of the gross tumor volume (GTV). The treatmentswere designed to cover 50% of the maximal dose to the margins of the target in a single frac-tion. The mean prescribed tumor volume was 21.2 cm3. The main prescription dose was 8 Gyof 3 fractions for three consecutive days (range, 5 to 8 Gy and 2 to 4 fractions for 2 to 4 conse-cutive days), using the same Leksell frame on the heads of the patients. The radiation dose wascalculated to biological equivalent dose (BED) using a/b ratio of 10 and single fraction equiva-lent dose (SFED) using Dq of 1.8 for analysis of dose related response. The fractionation radia-tion dose calculated to BED and SFED are summarized in Table 2.[18, 19]Follow up was typically conducted at one and three months after radiosurgery, followed by

MRI examinations at 3-month intervals. Additional neuroimaging was obtained if neurologicsigns or symptoms developed. The tumor volume was measured on the follow-upMRI scansas previously described. Local control failure was defined as an increase in tumor volume to>125% of that measured at the time of radiosurgery.[20] Distant control failure was defined asprogression in the brain but not within the radiosurgical target volume. Radiation-relatedbrain necrosis was thoroughly assessed using the T1/T2 mismatch on the MRI scan.[21]Although there is no clear criteria for defining radiation necrosis, we performed positron emis-sion tomography (PET) imaging for those with high possibility.[22] Surgical resectionwasencouragedwhen clinical signs of cerebral herniation or imminent herniation developed in thecontext of a radiographic diagnosis of local tumor progression or radiation necrosis during thefollow-up period. Treatment toxicity was also assumed when the Karnofsky performance statusscore decreased or when the neurologic signs or symptoms worsened, combined with a stable

Table 1. (Continued)

Characteristics Value

Covered ratio (%) 95–99

a Other histology include: 2 Squamous cell carcinoma, 2 Ovarian cancer, 1 Melanoma, 1 Hematologic

malignancy, 1 Ewing sarcoma, 1 Cervix cancer, 1 Unknown.

doi:10.1371/journal.pone.0163304.t001

Table 2. Fractionation radiation dose in BED and SFED.

Fractionation schedule Cases (%) BED10 SFED (Gy)

8 Gy x 3 24 (66.6) 43.2 20.4

10 Gy x 3 6 (16.6) 60 26.4

9 Gy x 3 2 (5.5) 51.3 23.4

5 Gy x 4 2 (5.5) 30 14.6

7 Gy x 3 1 (2.7) 35.7 17.4

11 Gy x 2 1 (2.7) 24.2 20.2

BED = Biological equivalent dose, SFED = Single fraction equivalent dose.

doi:10.1371/journal.pone.0163304.t002

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or decreasing contrast-enhancing lesion within the radiosurgical target volume with increasingperitumoral edema. Overall survival was defined as the interval between radiosurgery and thedeath of the patient. Kaplan-Meier survival plots were used to estimate the overall survival dis-tributions. The log-rank test (level of significance, p<0.05) was used to assess differences in theoverall survival distributions between the groups. The Cox proportional hazards model (levelof significance, p 0.05) was used to adjust for covariates, which were categorically tested. Allstatistical analyses were performed using IBM SPSS Statistics, version 22.0.0.1.

Results

The follow up period ranged from 1 to 51.9 months, with a median follow up period of 13.4months. The one-year and two-year overall survival rates were 66.7 and 33.1%, respectively,with a median survival time of 16.2 months. The local tumor control rate was 90%. Twentythree had died, and thirteen patients survived to the last follow up. Sixteen patients died of sys-temic progression, and seven patients died of neurological deterioration. New metastatic brainlesions were found in eleven patients: four patients with a single lesion and seven patients withmultiple lesions. These new lesions were treated with repeat GK SRS in four patients, WBRT inthree patients, surgical removal in one and conservativemanagement in three patients. Ofthese, four survived and seven died. The clinical course of the neurologic deficits is shown inTable 3. Symptoms such as headache, cranial nerve palsy and weakness were observed in 15patients before treatment. Among these patients, 10 patients showed improvement, 4 patientsremained stable and only 1 patient was aggravated. All follow-up was done within 1 or 3months after treatment. There were no cases of newly developed neurological deficit after SRS.Toxicity was classified using RTOG CNS toxicity criteria. [23] Grade 1 toxicity was observed

in 3 (8.3%) patients, grade 2 in 1 (2.7%) patient and grade 3 in 1 (2.7%) patient respectively.Radiation necrosis, which is classified as grade 4 toxicity in this criteria developed in 1 (2.7%)patient. That patient underwent surgical treatment and radiation necrosis was pathologicallyconfirmed. There were 4 patients suspicious of radiation necrosis by MR imaging and all ofthem underwent PET imaging. Other 3 patients showed true progression based on PET andthese cases were not pathologically confirmed.Two representative cases are shown in Figs 1 and 2.There was no significant difference in survival between single and multiple metastases

(p = 0.73) and between those who had no previous treatment and those who hadWBRT(p = 0.62). GPA scoring showed statistical significance related with survival (p = 0.002).Median survival according to the GPA score was 3.7 months for scores of 0–1, 17.9 months for

Table 3. Clinical course of neurologic deficits after SRS.

No. of patients Follow up

Improved Stable Worse

New deficit after SRS 0

No symptoms 21

Pre-existing symptoms 15

Headache 6 3 3 0

Motor/sensory deficit 7 5 1 1

Visual deficit 2 1 1 0

Dysphagia/dysarthria 2 2 0 0

Seizure 1 1 0 0

SRS = Stereotactic radiosurgery.

doi:10.1371/journal.pone.0163304.t003

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scores of 1.5–2.5, and 23 months for scores of 3–4. Univariate analysis revealed that primarydisease control (p = 0.001) and KPS score (p = 0.013) showed differences in survival outcomes.Lesions greater than 14 cm3 (3 cm in diameter), compared with smaller tumors, showed no sig-nificant differences in local control and overall survival.Multivariate analysis showed that con-trol of primary disease (p = 0.001; HR 0.16, 95% CI 0.04–0.33) and KPS�70 (p = 0.011; HR0.96, 95% CI 0.06–0.5) were significantly related to overall survival. The results of the statisticalanalyses are shown in Table 4.

Discussion

This study was designed to assess the efficacy, side effects and overall survival of patients withlarge metastatic brain lesions treated by gamma knife multi-fraction SRS for three to four

Fig 1. Illustrative cases of fractionated radiosurgery for large brain metastases. A 50-year-old woman

was diagnosed with brain metastases 4 years after treatment for breast cancer. She underwent surgical

removal at the time of diagnosis. (A) After 6 months she presented with progressive dysarthria, and follow-up

MRI showed recurrence. Radiosurgery was performed because of the post-operative recurrence and tumor

abutting the transverse sinus. The 16.5 cm3 cerebellar mass with was treated with a marginal dose of 8 Gy

targeted to the 50% isodose line in 3 consecutive daily fractions. (B) One month after radiosurgery, the

patient started systemic chemotherapy with Capecitabine, and the lesion dramatically decreased, and

neurological symptoms also improved. (C) A final follow-up image obtained 27 months after radiosurgery

shows that the lesion almost disappeared; the patient was still alive and on Gemcitabine and Cisplatin

chemotherapy due to primary disease progression at the time of analysis, which was 30 months after SRS.

doi:10.1371/journal.pone.0163304.g001

Fig 2. Another illustrative case of fractionated radiosurgery for large brain metastases. (A) A 53-year-

old man was diagnosed with brain metastases on a staging work-up for non-small cell lung cancer. The

lesion was 24.1 cm3; radiosurgery was performed with a marginal dose of 8 Gy targeted to the 50% isodose

line in 3 consecutive daily fractions. The patient was also started on Gefitnib chemotherapy. (B) After 1

month, the lesion dramatically decreased to 4.9 cm3. (C) After 3 months, the lesion decreased to 3.4 cm3.

The patient was later diagnosed with leptomeningeal carcinomatosis and was on Erlotinib chemotherapy at

the time of analysis, which was 8 months after SRS.

doi:10.1371/journal.pone.0163304.g002

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consecutive days using the same Leksell head frame. As described above, the treatment optionsfor brain metastases include surgical resection,WBRT and SRS. Metastatic lesion size, location,multiplicity, comorbidity, and performance status are considered important factors whendecidingwhich treatment options should be used.[6, 24, 25] Large metastases with mass effectand accessible location are good candidates for surgical resection. Lesions located in eloquentareas and patients in poor general condition are good candidates for radiosurgery;however,large size is a relative contraindication because of concerns regarding treatment-related toxicityincreased radiation exposure.[12] Because the selection criterion for SRS was traditionally lim-ited to lesions smaller than 3 cm, the treatment of choice for large metastases has typically beensurgical resection.Occasionally, palliativeWBRT or SRS was considered in inoperable cases.Radiosurgerywas originally defined as a conformal, single fraction of high dose radiation

using a stereotactic method aimed to destroy target tissue while preserving adjacent normal tis-sue.[26] Local control is highly dependent on the radiation dose and is known to be less effec-tive in single fraction doses lower than 15 Gy.[27, 28] The concept of radiosurgery has beenexpanded up to 5 fractions. The linear quadratic (LQ) model is used to calculate the biologiceffective doses (BEDs) and to compare different tissues with different doses and fractionation.[18] The α/β ratio for metastatic brain tumors is estimated from 10 to 20, and a high α/β ratioindicates increased sensitivity to multiple-session treatments.[29–31]Studies of single fraction SRS as a primary or salvage treatment for large brain metastases

have been reported in the literature. Clinical outcomes such as overall survival and local controlwere favorable, but the treatment-related toxicity was considerable. Lee et al. treated 109patients with a median dose of 18.0 Gy for a median tumor volume of 16.8 cm3, with progres-sive peritumoral edema in 19 (16.0%) patients.[32] Han et al. administered a single dose of 10–16 Gy to lesions with a mean volume of 22.4 cm3, and their results found unacceptable CNStoxicity of 18.8%. These authors suggested that a marginal dose of 11–12 Gy might be tolerabledue to the high rate of radiation toxicities.[33] CNS toxicity has diverse manifestations rangingfrommild, acceptable neurological symptoms to radiation necrosis and neurological deaths.The most significant risk factor for radiation necrosis is a high radiation dose in a large volumebecause the high dose eventually gives a high dose to the normal tissue in the periphery. TheRTOG protocol 90–05 reported that lesions with a maximal diameter of 3 cm or more shoulduse a maximal tolerated dose of 15 Gy due to toxicity.[23] Minniti et al. showed that a dose of12 Gy in lesions larger than 8.5 cm3 carries a risk of radiation necrosis of 10% or higher, andthe actuarial risk at 1 year was 24% for lesions 6.0–10.9 cm3 and 51% for those>10.9 cm3.[34]In this study as in Table 2, BED ranges from 24.2–60 and SFED ranges from 14.6–26.4 Gy.

Table 4. Prognostic factors related to overall survival of patients.

Univariate Multivariate

Variable HR P HR p 95% CI

Gender 1.401 .118

Age� 65 y 1.030 .179

KPS� 70 0.218 .013 0.957 .011 0.055–0.501

Control of primary disease 0.344 .001 0.166 .001 0.043–0.326

Extracranial metastases 1.305 .294

Multiple metastases 1.154 .732

Tumor volume > 14cm3 0.996 .984

HR = hazard ratio; CI = confidence interval; KPS = Karnofsky performance status.

doi:10.1371/journal.pone.0163304.t004

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Compared with previous single fraction studies, it can be suggested that hypofractionationradiosurgery has similar efficacy and paucity of treatment related toxicity.The significance of this study is the use of a daily fractionationmethod that was not previ-

ously reported in the literature. In fact, Gamma Knife-based SRS fractionated with intervalshas been reported for large metastatic lesions.[16, 17] Higuchi et al. used a regimen of 30 Gygiven in 3 fractions with a 2-week interval and showed promising results.[35] Yomo et al. per-formed two studies of fractionatedGamma Knife-based radiosurgerywith 20 to 30 Gy at the50% isodose line in two fractions, 3 to 4 weeks apart. One study of 27 patients with metastaticbrain lesions reported a one-year local control rate of 61% and an overall survival rate of 45%with one patient (3.5%) experiencing radiation injury.[16] Another study of 58 patients withmetastatic brain tumors reported a one-year local control rate of 64% and an overall survival of47% with three patients (5.1%) having radiation injury.[17] The strategy of those fractionatedGKS with an inter-fraction time of 2 to 4 weeks has the purpose of reducing tumor size so thatthe second treatment can be performed on a smaller volume more safely. In the current study,the overall survival rates at one and two years were 66.7 and 33.1%, respectively, and the medialsurvival time was 16.2 months. The local control rate was 90%, and radiation necrosis devel-oped in one (2.7%). Compared to previous studies, our study produced good clinical outcomeswith no significant difference in radiation-related toxicity; however, the interval and overalltreatment periodswere shorter in this study.[15–17, 36, 37] A daily consecutive treatmentschedule is appropriate in terms of its good efficacy and tolerable toxicity rate. The placementof a stereotactic frame for several days on the patient had been our concern for this treatment;however, headache, pain or discomfort was tolerable. Another concern was moving of targetbetween each fraction, and treatment location was confirmed by performing fusion of scoutimages.Surgical resection is often used as a primary or adjuvant treatment option. Rapid decom-

pression of mass effect is the strong merit of surgery in large tumors. However, surgery is diffi-cult in some cases due to tumor size, the eloquent location of the lesion and perioperativecomplications. In eloquent area lesions, postoperative neurological deficit is a major concern.Obermueller et al. analyzed 56 patients with motor cortex metastatic lesions; 12 patients(21.4%) showed aggravated paresis, which remained permanently in 7 patients (12.5%).[38]Paek et al. reported surgical outcomes in a series of 208 patients with single or multiple metas-tases; the operative mortality rate was 1.9%, and neurological deterioration occurred in 13patients (6%). There were also postoperative wound-related or systemic complications such assepsis, pneumonia, or deep vein thrombosis in 21 patients (10%).[39] In the present study,there were no new neurologic deficits after the procedure, and pre-existing symptoms weremostly improved or at least stable, as shown in Table 3. Thus, it is difficult to conclude thatradiosurgery is superior to surgery in terms of efficacy, but it is definitely a safer method interms of immediate perioperative complications.SRS to the resection cavity as an adjuvant to surgery is another treatment option. The pur-

pose of this method is to improve the local control rate and decrease the need for WBRT. Sev-eral reports showed satisfactory outcomes, including in terms of local control. [40–43]Compared with the surgery-only group, the adjuvant SRS group had a significantly lower localfailure rate; it can therefore be assumed that SRS is beneficial for local control.[42] One studyused 9 Gy in 3 fractions to resection cavities larger than 3 cm in diameter and also showedgood local control and low toxicity rates.[40] In our study, fractionated SRS was used as the pri-mary treatment option, and the local control rate was similar to that of surgery plus adjuvantSRS. In patients with an inoperable condition or lesion, fractionated SRS as a primary treat-ment option should be considered.

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LINAC-based, Cyberknife-fractionatedradiosurgery has also been reported in many stud-ies. The results show a local control of 70 to 96%, a median survival of 7 to 13.5 months and aradiation-related side effect rate of 5–10%.[8–11] Inoue et al. performed fractionationwithCyberknife, and the marginal dose ranged from 25–40 Gy with 50–75% isodose line.[44] Theadvantage of the Gamma Knife method allows a steeper dose fall-off so that a lower marginaldose can be prescribedwith easier treatment planning compared to LINAC-based methods,which can help spare normal structures.[45]This study was conducted in a retrospectivemanner with small number of cases with het-

erogeneous patients. Correlation of toxicity between single and hypofractionationmay be notclear because this study does not have control group and have small number of cases. RTOGtoxicity criteria was used for evaluation of treatment related toxicity but use of other QOLinstruments and neurocognitive assessment should have been used for more accurate interpre-tation of toxicity which is also another limitation.We did not perform statistical comparison ofvarious regimens. The optimal dose regimen is still unknown. Future prospective studies withlarge patient populations are needed to conclude that it is a safe and effectivemethod of treat-ment. This study should serve as basis for prospective study.

Conclusion

In this study, we demonstrated the efficacy and safety of hypofractionated Gamma Knife radio-surgery to treat large metastatic brain tumors or lesions located in the eloquent areas for threeconsecutive days with the same Leksell head frame. This result suggests that consecutive hypo-fractionatedGamma Knife SRS could be applied to large metastatic brain tumors with effectivetumor control and low toxicity rates.

Author Contributions

Conceptualization: JWKHRP JMLHTC SHP.

Data curation: JWKHRP JML.

Formal analysis: JWK SHP.

Funding acquisition: SHP.

Investigation: SHP.

Methodology: JWKDGKHWJ SHP.

Project administration: SHP.

Resources: JWK SHP.

Software:HTC SHP.

Supervision: JWKHTC DGKHWJ SHP.

Validation: SHP.

Visualization: JWK SHP.

Writing – original draft: JWK.

Writing – review& editing: JWKHRP JML SHP.

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